Go 6976 is a potent inhibitor of neurotrophin-receptor intrinsic tyrosine kinase

We report here that addition of the protein kinase C inhibitor Gd 6976 blocked neurotrophin-induced signaling and autophosphorylation of neurotrophin-specific tyrosine kinase (Trk) receptors, either Trk B in cortical neurons or Trk A in GT1-1-trk9 cells, The effect of Go 6976 on Trk autophosphorylation was not inhibited by 100 mu M orthovanadate, suggesting that the block was not due to the activation of tyrosine phosphatases, Moreover, addition of 10-100 nM concentrations of Go 6976 inhibited either Trk B or Trk A intrinsic kinase activity in cell-free assays, Gb 6976 also blocked the ability of brain-derived neurotrophic factor to promote cortical neuronal survival and the ability of nerve growth factor to promote PC12 cell survival and differentiation. These results suggest that Go 6976, besides its known inhibitory effects on lipid- and calcium-dependent isoforms of protein kinase C, can also inhibit neurotrophin signaling by directly inhibiting the intrinsic Trk.